The present invention relates generally to vaccines against Bordetella species that include interleukin-12 (IL-12) as an adjuvant, and to methods for using IL-12 as an adjuvant in or in combination with such vaccines.
Colonization of the respiratory tract by the Gram-negative coccobacillus Bordetella pertussis results in whooping cough, also called pertussis, a significant cause of morbidity and mortality of human infants. Two other closely-related isolates of Bordetella have also been found in humans: B. parapertussis and B. bronchiseptica. Molecular genetic analyses suggests that these three isolates are too closely related to be classified as separate species. (Gilchrist, M. J. R., 1991, “Bordetella”, in Manual of Clinical Microbiology, 5th ed., Balows, A. et al., American Society for Microbiology, Washington, D.C.) While B. pertussis differs from B. bronchiseptica and B. parapertussis in the nature of the toxins it produces, B. bronchiseptica and B. parapertussis do produce active toxins (Hausman, S. Z. et al., 1996, Infect. Immun. 64: 4020-4026), and there is some evidence to indicate that B. pertussis organisms can covert to the B. parapertussis phenotype (Gilchrist, M. J. R., 1991, “Bordetalla”, in Manual of Clinical Microbiology, 5th ed., Balows, A. et al., eds., American Society for Mircobiology, Washington, D.C.). Although Bordetalla isolates exhibit some surface antigens that differ between isolates, monoclonal antibodies that recognize one isolate often recognize at least one other isolate (LeBlay, K. et al., 1996, Microbiology 142: 971-978). The high degree of molecular similarity between Bordetella isolates and the cross-reactivity of monoclonal antibodies to Bordetella antigens indicates that the immune response product by a vaccine against one Bordetella isolate would likely affect the other isolates as well.
Immunization with a whole-cell Bordetella pertussis vaccine have proved efficacious in controlling pertussis, but concern has been raised over its reactogenicity. Pertussis acellular vaccines are significantly less reactogenic but are of varying efficacy. Until recently the bacterium was thought to occupy a purely extracellular niche during infection and consequently humoral immune mechanisms were assumed to be paramount in protection. (Robinson, A. et al., 1985, Vaccine 3: 11-22). However, there is increasing evidence from human and murine studies that B. pertussis can also occupy an intracellular niche through invasion and survival within lung macrophages and other cell types. (Friedman, R. L. et al., 1992, Infect. Immun. 60: 4578-4585; Saukkonen, K. et al., 1991, J. Exp. Med. 173: 1143-1149). These observations have let to a reexamination of the mechanisms of protective immunity against B. pertussis. While antibody plays a role in bacterial toxin neutralization and in the prevention of bacterial attachment following transudation of circulating immunoglobulin (lg) into the lung, cell-mediated immunity also plays a significant role in protection against B. pertussis (Mills, K. H. G. and K. Redhead, 1993, J. Med. Microbiol. 39: 163-164; Peppoloni, S. et al., 1991, Infect. Immun. 59: 3768-3773; Peterson, J. P. et al., 1992, Infect. Immun. 60: 4563-4570.)
The current understanding of the role of CD4+T helper (Th) cells in immunity to infectious diseases is that antigen-specific type 1 T helper (Th1) cells which secrete interferon-γ (IFN-γ), interleukin-2 (IL-2), and tumor necrosis factor-β (TNF-β) mediate cellular immunity, delayed-type hypersensitivity, and inflammatory responses, whereas type 2 T helper (Th2) cells which secrete the interleukins IL-4, IL-5, and IL-6 are considered to be mainly responsible for the provision of specific T cell help for antibody production. (Mosmann, T. R. and R. L. Coffman, 1989, Adv. Immunol. 46: 111-147.) Previous studies using a murine respiratory model have demonstrated that protective immunity against B. Pertussis induced by infection is mediated by a CD4+ T cell population that secreted IL-2 and IFN-γ (Th1 cells). Adoptive transfer experiments demonstrated that protection could be conferred with T cells in the absence of detectable antibody responses. In a study of vaccine-induced immunity, immunization with the whole-cell pertussis vaccine selectively induced Th1 cells, whereas an acellular vaccine, comprising the B. pertussis antigens detoxified PT, FHA, and pertactin, induced Th2 cells. Furthermore, the induction of a Th1 response following infection or immunization with the whole-cell vaccine was associated with earlier bacterial clearance following respiratory challenge. (Mills, K. H. G. et al., 1993, Infect. Immun. 61: 399-410; Redhead, K. et al., 1993, Infect. Immun. 61: 3190-3198.)
The polarization of CD4+ T cell cytokine production towards type 1 or type 2 responses following in vivo priming appears to be controlled by a number of factors including the nature of the immunogen, the route of immunization, and the antigen-presenting cell and regulatory cytokine milieu at the site of T cell stimulation. (Barnard, A. et al., 1996, Immunol. 87: 372-380; Gajewski, T. F. et al., 1991, J. Immunol. 146: 1750-1758; O'Gara, A. and K. Murphy, 1994, Curr. Opin. Immunol. 6: 458-466.) The regulatory cytokine interleukin-12 (IL-12) is also a key cytokine in the development of type 1 responses. (Hsieh, C.-S. et al., 1993, Science 260: 547-549; Trinchieri, G., 1995, Annu. Rev. Immunol. 13: 251-276.) IL-12 can induce the secretion of IFN-γ by natural killer (NK) cells and by CD4+T cells and can promote the differentiation and development of Th1 cells from Th0 precursor populations. (Bliss, J. et al., 1996, J. Immunol. 156: 887-894; McKnight, A. J. et al., 1994, J. Immunol. 152: 2172-2179; Seder, R. A. et al., 1993, PNAS USA 90: 10188-10192.) Furthermore, IL-12 may also induce the production of opsonizing antibodies, by promoting IFN-γ-mediated immunoglobulin (Ig) class switching in favor of IgG2a in the mouse. (Morris, S. C. et al., 1994, J. Immunol. 152: 1047-1056.) Since Th1 cells play an important role in the resolution of infections with intracellular organisms, IL-12 can influence the course of bacterial, viral, and parasitic infections by altering the balance of Th1 and Th2 cells in favor of IFN-γ production. (Flynn, J. L. et al., 1995, J. Immunol. 155: 2515-2524; Gazzinelli, R. T. et al., 1993, PNAS USA 90: 6115-6119; Heinzel, F. P. et al., 1993, J. Exp. Med. 177: 1505-1509; Hunter, C. A. et al., 1994, Infect. Immun. 62: 2818-2814; Sypek, J. P. et al., 1993, J. Exp. Med. 177: 1797-1802; Tripp, C. S. et al., 1994, J. Immunol. 152: 1833-1887; Urban, J. F. et al., 1996, J. Immunol. 156: 263-268; Wynn, T. A. et al., 1994, J. Exp. Med. 179: 1551-1561; Zhan, Y. and C. Cheers, 1995, Infect. Immun. 63: 1387-1390.)
There is a continuing requirement for new composition comprising IL-12 that will enhance or alter the effects of Bordetella vaccines, and for methods for their use in the prevention, treatment, or amelioration of Bordetella infections.